Sonesitatug Vedotin Improves Survival in Phase III Gastric Cancer Trial

AstraZeneca reported positive high-level results from the global Phase III CLARITY-Gastric01 trial (NCT06346392) showing that sonesitatug vedotin (Sone-Ve) significantly improved overall survival (OS) in patients with previously treated CLDN18.2-positive locally advanced or metastatic gastric cancer, gastroesophageal junction (GEJ) cancer, and esophageal adenocarcinoma (EAC). The investigational antibody-drug conjugate met its dual primary overall survival endpoint in the third line and later (3L+) treatment setting and achieved a key secondary endpoint by improving overall survival in the broader second-line and later (2L+) population.

The study also evaluated progression-free survival (PFS) as a co-primary endpoint in the overall 2L+ population. Although PFS showed a trend toward improvement, it did not reach statistical significance, providing important context for interpreting the trial’s efficacy outcomes.

Scientific and Clinical Context

Sonesitatug vedotin is an investigational CLDN18.2-targeted antibody-drug conjugate (ADC) comprising an anti-CLDN18.2 monoclonal antibody linked through a protease-cleavable linker to the cytotoxic payload monomethyl auristatin E (MMAE). CLDN18.2 is a tight junction protein selectively expressed in gastric mucosa and frequently retained in gastric and gastroesophageal tumors, making it an attractive therapeutic target.

Advanced gastric and GEJ cancers remain among the deadliest gastrointestinal malignancies. Most patients experience disease progression after first-line therapy, and median survival following second- or later-line systemic treatment typically ranges from five to nine months.

CLDN18.2 has emerged as an important biomarker for targeted therapy. CLARITY-Gastric01 enrolled patients whose tumors expressed CLDN18.2 in at least 25% of tumor cells at any staining intensity, a lower expression threshold than earlier CLDN18.2-targeted treatment strategies. If validated through regulatory review, this broader biomarker definition could expand eligibility for targeted therapy to approximately 60% of patients with gastric and GEJ cancers.

The trial will also support evaluation of the Ventana SP455 assay as a companion diagnostic to identify patients with advanced gastric, GEJ, or esophageal adenocarcinomas who may benefit from Sone-Ve. Across the United States, European Union, China, and Japan, an estimated 183,500 patients receive second- or later-line treatment each year for advanced CLDN18.2-positive, HER2-negative gastric and GEJ cancers, highlighting a substantial unmet medical need.

Phase III CLARITY-Gastric01 Results

CLARITY-Gastric01 is a randomized, open-label, sponsor-blinded, global Phase III trial evaluating Sone-Ve in patients with previously treated advanced or metastatic gastric cancer, GEJ cancer, or EAC expressing CLDN18.2 in at least 25% of tumor cells.

The trial met its dual primary endpoint of overall survival in the 3L+ setting, demonstrating a statistically significant and highly clinically meaningful improvement compared with investigator’s choice of therapy. It also met a key secondary endpoint by significantly improving overall survival in the broader 2L+ population.

The co-primary endpoint of PFS, assessed by blinded independent central review (BICR), showed a trend toward improvement in the 2L+ population but did not achieve statistical significance. Nevertheless, the overall survival benefit suggests clinically meaningful activity in a patient population with limited treatment options following first-line therapy.

Sone-Ve was generally well tolerated, with a safety profile consistent with previous clinical experience and no new safety signals identified.

Clinical Implications

Rui-Hua Xu, MD, PhD, Professor of Medical Oncology at Sun Yat-Sen University Cancer Center and principal investigator of the study, said the findings address a major unmet need for patients with metastatic gastric cancer who progress after first-line treatment. He noted that Sone-Ve is the first CLDN18.2-targeted ADC to demonstrate an overall survival benefit in this setting and has the potential to establish a new precision medicine option for patients with CLDN18.2-positive disease.

Susan Galbraith, Executive Vice President, Oncology Haematology R&D at AstraZeneca, said the results demonstrate the potential of targeted antibody-drug conjugates to improve outcomes beyond conventional chemotherapy. She added that CLARITY-Gastric01 represents the first pivotal Phase III readout from AstraZeneca’s wholly owned ADC portfolio and supports the broader development program for Sone-Ve.

Regulatory Path Forward

The full CLARITY-Gastric01 results will be presented at an upcoming scientific meeting and submitted to global regulatory authorities. These findings may support future regulatory filings for Sone-Ve in previously treated CLDN18.2-positive gastric and gastroesophageal cancers.

Sone-Ve has received Orphan Drug Designation from both the U.S. Food and Drug Administration and the European Commission for the treatment of gastric and GEJ cancers. It has also received Breakthrough Designation in China for second-line gastric cancer.

AstraZeneca is continuing development through the Phase III CLARITY-Gastric02 trial, which is evaluating Sone-Ve in combination with capecitabine, with or without rilvegostomig, as a first-line treatment for advanced gastric cancer, GEJ cancer, and EAC. Additional Phase II studies are exploring the ADC in other CLDN18.2-positive solid tumors, including pancreatic and biliary tract cancers, further defining its potential role across gastrointestinal oncology.

Reference

Sonesitatug vedotin demonstrated a statistically significant and highly clinically meaningful improvement in overall survival in 2nd and later-line CLDN18.2-positive advanced gastric/GEJ cancers